This application is a 371 of PCT/JP96/02231 filed Aug. 2, 1996 claiming Patent from Japanese Patent Application No. 7-207050 filed Aug. 7, 1995.
The present invention relates to drugs for prevention or treatment of diseases caused by abnormalities in cartilage tissues, containing an omega-9 unsaturated fatty acid as an active ingredient, and foods and drinks having the effect of preventing or alleviating medical conditions caused by abnormalities in cartilage tissues, and to a process for producing said drugs. More specifically, the present invention relates to drugs for prevention or treatment of diseases associated with cartilage degeneration such as arthropathy, osteoarthritis, gonarthrosis, periarthritis scapulo-humeralis, spondylitis deformans, etc. and foods or drinks having the effect of preventing or alleviating joint pains, cinealgia, limited range of motion of joints, swelling joints or hydrarthrosis, etc. containing as an active ingredient at least one compound selected from the group consisting of 6,9-octadecadienoic acid, 8,11-eicosadienoic acid, and 5,8,11-eicosatrienoic acid, and to a process for producing them.
Arthropathy has been divided into the secondary arthropathy that occurs as a sequela to some underlying disease that causes cartilage degeneration, and the primary arthropathy having no specific underlying diseases. Arthropathy is seen most frequently in the knee joints, and less frequently in the joints of elbow, hip, legs, and fingers. A change to a morbid state causes mainly degeneration of cartilage and the repairing mechanism thereof. The progress of the morbid state leads to changes in synovial membrane, destruction of subchondral bones, cartilage hypertrophy in the joint margins, or neogenesis of bone.
Osteoarthritis is a disease in which chronic degenerative changes and proliferative changes take place simultaneously in joints leading to changes in morphology of joints, and is roughly classified into the primary osteoarthritis and the secondary osteoarthritis. The former is more frequently seen in and after middle ages, wherein aging processes combined with mechanical stress lead to its onset, and the latter is seen in the young generation as well, with its onset being secondary to some evident etiology such as joint trauma, morphological abnormalities, diseases, metabolic disorders, etc. Histologically it is characterized by cartilage abrasion as a result of biochemical changes of cartilage, with cleavage as well as reduced viscoelasticity of cartilage reaching the deep part. Spondylosis deformans is a degenerative lesion of the spine. Although its main cause is age change, involvement of constitutional disposition, environmental factors such as occupation, trauma in a broader sense, etc. has been implicated (cited from xe2x80x9cMedical Dictionary, published on Mar. 25, 1991, Nannzanndoxe2x80x9d).
Especially, with regard to the primary osteoarthritis, the increasing number of patients due to underlying causes of aging of the population has become a major social problem. As a medicinal treatment of osteoarthritis, administration of nonsteroidal anti-inflammatory drugs, intra articular injection of steroids, etc. have been employed in order to prevent inflammation of articular cartilage and periosteum, but these are all symptomatic treatments and, therefore, have not been very successful at present for arresting the progress of cartilage destruction.
As a protection against extraneous cartilage destruction due to mechanical stress etc., a high-molecular hyaluronic acid preparation has been used, but it cannot be considered an essential method of treatment. Ameliorating drugs of endogeneous cartilage destruction due to metabolic disorders of chondrocytes themselves which are becoming evident in the recent progress of biochemical research on chondrocytes, and drugs for causative treatment such as would regenerate cartilage loss or destruction often occurring in osteoarthritis have not been known, and its development has been strongly desired.
Thus, it is an object of the invention to provide drugs that are useful for prevention or treatment of diseases caused by abnormalities in cartilage tissues, in particular, for prevention of disease associated with cartilage degeneration such as, in particular, arthropathy, osteoarthritis, periarthritis scapulo-humeralis, spondylitis deformans, etc. and that have relatively small side effects, and thus are applicable to chronic disorders, and new foods and drinks having the effect of preventing or alleviating medical conditions caused by abnormalities in cartilage tissues.
Cartilage tissues are avascular, which is extremely uncommon as a tissue derived from a mesenchyma, and even normal cartilage tissues contain lipids (Ann. Rheum. Dis., 24, 123-135, 1965). However, excessive accumulation of lipids may be observed as pathomorphism in lipo-hem arthropathy (J. Bone Joint Surg. [Am] 52, 1147-1158, 1970) and precocious arthropathy (Arthritis Rheum. 24, 965-968, 1981). In addition, correlation of abnormal metabolism of lipids with medical conditions has been reported in osteoarthritis as well (Metabolism, 40, 571-576, 1991).
An appropriate amount of lipids and appropriate composition of fatty acids are considered to be important for maintenance of normal metabolism and functions of chondrocytes based on the reports that administration of lipids into a joint of rabbit can induce experimental osteoarthritis-like arthropathy (J. Anat, 133, 309-314, 1981), and can reduce chondral incorporation of 35SO4 in essential fatty acids-deficient Wistar rats (Arthritis Rheum., 14, 379, 1971), and that lipid supply is needed for normal growth of chondrocytes (Exp. Cell. Res., 145, 415-423, 1983).
However, the role of the above changes in lipids in initiation and aggravation processes of arthropathy has not been fully studied, and furthermore it is not clear whether the administration of lipids is effective for treatment of arthropathy, especially, osteoarthritis. On the other hand, omega-9 unsaturated fatty acids are known to be localized in cartilage tissues and its contents decrease with aging (FASEB J., 5,344-353, 1991), and believed to be important for maintenance of functions of chondrocytes. Furthermore, 5,8,11-eicosatrienoic acid has been confirmed to have an anti-inflammatory effect on the rat models of carrageenan-induced edema, but its pharmaceutical actions in arthropathy is little known.
Thus, in order to resolve the above problems, the inventors have carried out studies on various unsaturated fatty acids and consequently found that 5,8,11-eicosatrienoic acid has an action of inhibiting cartilage degeneration and that hence it is very useful for prevention or treatment of diseases caused by abnormalities in cartilage tissues, and we have completed the present invention.